CN1376160A - Novel macrolide antibiotics - Google Patents

Novel macrolide antibiotics Download PDF

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CN1376160A
CN1376160A CN99812941A CN99812941A CN1376160A CN 1376160 A CN1376160 A CN 1376160A CN 99812941 A CN99812941 A CN 99812941A CN 99812941 A CN99812941 A CN 99812941A CN 1376160 A CN1376160 A CN 1376160A
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alkyl
aryl
methyl
heteroaryl
hydrogen
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金子卓史
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Pfizer Products Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08Hetero rings containing eight or more ring members, e.g. erythromycins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/14Antitussive agents
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/02Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • AHUMAN NECESSITIES
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/02Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

This invention relates to compounds of formula I wherein a, R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and X are each as defined above, and to pharmaceutically acceptable salts thereof, useful as potent antibacterial and antiprotozoal agents that may be used to treat various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula I and to methods of treating bacterial and protozoal infections by administering the compounds of formula I.

Description

New macrolide antibiotic
Background of invention
The present invention relates to new macrolide derivatives, can be used as the Mammals that comprises the people and antibacterium and the antiprotozoal of fish and birds.The present invention also relates to contain the pharmaceutical composition of this new compound, with bacterium and the protozoal infections of treatment Mammals, fish and birds and with infectation of bacteria the method for relevant illness, for example atherosclerosis and cancer, this method are Mammals, fish and the birds administrations to this treatment of needs of compound that this is new.
Known macrolide antibiotic can be used for the treatment of Mammals, fish and birds broad spectrum of bacteria and protozoal infections.Such microbiotic comprises the various derivatives of Erythromycin A, azithromycin for example, and it is commercial available, referring to United States Patent (USP) 4474768 and 4517359, the two quotes in full at this as a reference.As azithromycin and other macrolide antibiotic, new Macrocyclic lactone compounds of the present invention also is the wide spectrum macrolide antibiotic, effectively resists the infection that is caused by some Gram-positive and gram negative bacterium and protozoon.
Summary of the invention
The present invention relates to following formula: compound
Figure A9981294100171
Or its pharmacy acceptable salt; Wherein the dotted line between 10 and 11 is represented optional double bond; A is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be amino, cyano group, N 3, R 10NH, R 10C (O) NH, R 10NHC (O) NH, R 10NHC (S) NH, R 10NHNHC (O) NH, R 10ONHC (O) NH, R 10O, R 10OC (O) NH, R 10S (O) n, R 10Phosphinylidyne amino, R 10Sulfonamido, SH, R 10S, n definition wherein is the same, R 10Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl; Perhaps R 3Be R 12R 13N, R wherein 12And R 13Be hydrogen, (C independently of one another 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl;
R 4Be hydrogen, optional by one or two nitro, cyano group, R 14C (O) and R 14The methyl that OC (O) replaces; Perhaps R 4Be N 3, R 14O, R 14NH, R 14S, R wherein 14Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl; Perhaps R 4Be R 15N (C 1-C 6) alkyl, R wherein 15Be hydrogen, (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl;
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
Perhaps R 3And R 4Can form with the carbon that they connected
Figure A9981294100191
Wherein the dotted line between nitrogen in formula II and the variable group W is represented optional double bond;
W is C=O, C=S, SO 2Or C=NR 10, R wherein 10Define the same;
Y is oxygen, sulphur or NR 17, R wherein 17Be hydrogen, R 19, R 19O or R 19NH, R wherein 19Be hydrogen, (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 5-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 18Be hydrogen, (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, aryl wherein and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 20R 21N, R 20C (O), R 20C (O) O, R 20OC (O), R 20C (O) NH, R 20NHC (O), R 20R 21NC (O) and R 20OC (O) 2, R wherein 20And R 21Be hydrogen, optional quilt (C independently of one another 6-C 10) acyl group or (C 5-C 10) (the C that replaces of aryl 1-C 6) alkyl or (C 2-C 9) heteroaryl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement;
Its condition is R 17Or R 18Have at least one to be hydrogen;
If its condition is dotted line representative two key, then R between 10 and 11 4Be hydrogen;
Its condition is if a is zero, then R 1Be hydrogen.
Term used herein " alkyl " unless indication is arranged in addition, comprise have straight chain, the saturated monovalence alkyl of side chain or cyclic group.Self-evidently concerning cyclic group be, need at least three carbon atoms in described alkyl, self-evident concerning the described alkyl that comprises carbon-to-carbon double bond or three key is to need at least two carbon atoms in described alkyl.
Term used herein " hydroxy-protective group " comprises benzoyl, benzyl, (C unless indication is arranged in addition 1-C 6) alkyloyl, ((C 1-C 3) alkyl) 3Silyl and t-butyldimethylsilyl are preferably ethanoyl.Alkyloyl can cracking after as the prodrug administration.
Term used herein " aryl " comprises from aromatic hydrocarbons and removes a hydrogen and deutero-organic group, for example phenyl or naphthyl unless indication is arranged in addition.
(C used herein 2-C 9) Heterocyclylalkyl refers to pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, THP trtrahydropyranyl, pyranyl, the thiapyran base, aziridinyl, Oxyranyle, methylene-dioxy, benzopyranyl isoxazole alkyl, 1,3-oxazolidine-3-base, the isothiazole alkyl, 1,3-thiazolidine-3-base, 1,2-pyrazolidine-2-base, 1,3-pyrazolidine-1-base, piperidyl, thio-morpholinyl, 1,2-tetrahydrochysene thiazine-2-base, 1,3-tetrahydrochysene thiazine-3-base, tetrahydrochysene thiadiazine base, morpholinyl, 1,2-tetrahydrochysene diazine-2-base, 1,3-tetrahydrochysene diazine-1-base, tetrahydrochysene azatropylidene base, piperazinyl, chromanyl etc.Those of ordinary skills will figure out, described (C 2-C 9) heterocycloalkyl ring is by carbon atom or sp 3The hydridization nitrogen heteroatom connects.
(C used herein 2-C 9) heteroaryl refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl oxazolyl isoxazolyl, pyrryl, triazolyl, tetrazyl, imidazolyl, 1,3,5-oxadiazole base, 1,2,4-oxadiazole base, 1,2,3-oxadiazole base, 1,3, the 5-thiadiazolyl group, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2, the 4-triazinyl, 1,2, the 3-triazinyl, 1,3, the 5-triazinyl, pyrazolo [3,4-b] pyridyl, the cinnolines base, pteridyl, purine radicals, 6,7-dihydro-5H-[1] indyl, benzo [b] thienyl, 5,6,7,8-tetrahydroquinoline-3-base benzoxazolyl, benzothiazolyl, the benzisothiazole base, the benzoisoxazole base, benzimidazolyl-, thianaphthenyl, the isothianaphthene base, benzofuryl, isobenzofuran-base, pseudoindoyl, indyl, the indolizine base, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolyl benzoxazinyl etc.Those of ordinary skills will figure out, described (C 2-C 9) heteroaryl ring is by carbon atom or sp 3The hydridization nitrogen heteroatom connects.
Term used herein " acyl group " comprises general formula R CO group unless indication is arranged in addition, and wherein R is alkyl, alkoxyl group, aryl, aralkyl or aralkoxy, and term " alkyl " or " aryl " definition are the same.
The location definition of formula I macrolide derivatives is as follows:
Figure A9981294100221
The compounds of this invention comprises all configurational isomers (for example cis and trans-isomer(ide)) and all optically active isomers (for example enantiomorph and diastereomer) of formula I compound, and the racemic mixture of these isomer, non-enantiomer mixture and other mixture.
Wording used herein " pharmacy acceptable salt " comprises the acidity that may reside in the The compounds of this invention or the salt of basic group unless indication is arranged in addition.The The compounds of this invention of alkalescence can form multiple salt with various inorganic and organic acids.The acid that can be used for preparing the pharmaceutically-acceptable acid addition of these basic cpds is to form those of nontoxic acid salt, promptly contain pharmaceutically acceptable anionic salt, hydrochloride for example, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, Citrate trianion, the acid Citrate trianion, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and pamoate (promptly 1,1 '-methylene radical-two (2-hydroxyl-3-naphthoate)).Except above-mentioned acid, comprise that the The compounds of this invention of amino group can also form pharmacy acceptable salt with each seed amino acid.
The tart The compounds of this invention can form alkali salt with various pharmaceutically acceptable positively charged ions.The example of these salt comprises the basic metal or the alkaline earth salt of The compounds of this invention, exactly is calcium salt, magnesium salts, sodium salt and sylvite.
Some The compounds of this invention can have asymmetric center, therefore exists with different mappings and diastereomeric form formula.The present invention relates to the purposes of all optically active isomers of The compounds of this invention and steric isomer and composition thereof, relate to all pharmaceutical compositions and the methods of treatment that can adopt or contain them.
The present invention includes such The compounds of this invention and pharmacy acceptable salt thereof, wherein one or more hydrogen, carbon or other atom are replaced by its isotropic substance.Such compound can be used as research and diagnostic tool in the metabolism pharmacokinetic studies with in conjunction with in measuring.
Preferred formula I compound comprises that wherein a is 1 and R 1Be (C 1-C 10) those of alkyl.
Other preferred formula I compound comprises wherein R 2Be those of hydrogen.
Other preferred formula I compound comprises wherein R 3Be N 3, R 10NH, R 10C (O), R 10NHC (O) NH or R 10Those of NHNHC (O) NH.
Other preferred formula I compound comprises wherein R 4Be hydrogen, R 14NH or R 14Those of S.
Other preferred formula I compound comprises wherein R 6Be those of ethyl.
Other preferred formula I compound comprises that wherein W is that C=O and Y are NR 17Those.
Preferred formula I compound comprises that wherein a is 1; R 1Be (C 1-C 10) alkyl; R 2Be hydrogen; R 3Be N 3, R 10NH, R 10C (O), R 10NHC (O) NH or R 10NHNHC (O) NH; R 4Be hydrogen, R 14NH or R 14S and R 6Be those of ethyl.
Preferred formula I compound comprises that wherein a is 1; R 1Be (C 1-C 10) alkyl; R 2Be hydrogen; R 3And R 4Form formula II compound with the carbon that they connected; W is that C=O and Y are NR 17Those.
Concrete preferred formula I compound comprises as follows:
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2,11-(imino-carbonyl (2-(3-(4-quinolyl) propyl group) hydrazono-))-3-oxo erythromycin;
11,12-dideoxy-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11,12-dideoxy-11,12-two dehydrogenations-3-takes off ((2, the 6-dideoxy-own ribose of 3-C-methyl-3-O-methyl-α-L-pyrans-5-yl) oxygen)-6-O-methyl isophthalic acid 0-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo-8-and show erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo-8-erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo-12,11-(imino-carbonyl hydrazono-) erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-imino-carbonyl hydrazono--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-isothiocyanato-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-alkynes propoxy--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate; With
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate.
The present invention also relates to be used for the pharmaceutical composition of Mammals, fish or birds treatment for diseases, these illnesss are selected from infectation of bacteria, protozoal infections or the illness relevant with infectation of bacteria or protozoal infections, and this pharmaceutical composition comprises formula I compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
The present invention also relates to treat the method for Mammals, fish or birds illness, these illnesss are selected from infectation of bacteria, protozoal infections or the illness relevant with infectation of bacteria or protozoal infections, and this method comprises the formula I compound of significant quantity on the therapeutics or its pharmacy acceptable salt described Mammals, fish or birds administration.
The present invention also relates to be used for Mammals, particularly people's cancer, the particularly pharmaceutical composition of nonsmall-cell lung cancer treatment, this pharmaceutical composition comprises formula I compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
The present invention also relates to treat the method for mammalian cancer, particularly nonsmall-cell lung cancer, this method comprises the formula I compound of significant quantity on the therapeutics or its pharmacy acceptable salt described Mammals administration.
Verb used herein " treatment " refers to reverse, alleviate, suppress the progress of illness that this term is suitable for or disease or prevents it unless otherwise specified, perhaps at one or more symptoms of this illness or disease.Noun used herein " treatment " refers to as the behavior of defined verb " treatment " just now.
Unless otherwise specified, term used herein or wording " infectation of bacteria ", " protozoal infections " comprise as follows with " illness relevant with infectation of bacteria or protozoal infections ": infect relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and mastoiditis with streptococcus pneumoniae, hemophilus influenzae, Moraxella catarrhalis, streptococcus aureus or peptostreptococcus; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis with streptococcus pyogenes, C family and G family suis, diphtheria clostridium (clostridiumdiptheriae) or Actinobacillus haemolyticum; The respiratory tract infection relevant with mycoplasma pneumoniae, legionella pneumophilia, streptococcus pneumoniae, hemophilus influenzae or infection involving chlamydia pneumoniae; With streptococcus aureus, coagulase-positive staphylococci (being staphylococcus epidermidis, staphylococcus haemolyticus etc.), streptococcus pyogenes, streptococcus agalactiae, suis C-F family (minute-colony streptococci), viridans streptococci (viridans streptococci), minimum coryneform bacteria (Corynebacterium minutissimum), clostridium or relevant non-concurrency skin and soft tissue infection, abscess and osteomyelitis and the lochiopyra of Bartonella henselae; Infect relevant uncomplicated acute urinary tract infection with Staphylococcus saprophyticus or faecalis; Urethritis and trachelitis; Infect relevant sexually transmitted disease (STD) with chlamydia trachomatis, Ducrey bacillus, Tyreponema pallidum, Ureaplasma urealyticum or Diplococcus gonorrhoeae; With streptococcus aureus (food poisoning and toxic shock syndrome) or A, the B toxin disease relevant with the streptococcal infection of C family; The ulcer relevant with helicobacter pylori infection; Infect relevant whole body heating syndrome with borrelia obermeieri; Infect relevant Lyme disease with Borrelia burgdofferi; Infect relevant conjunctivitis, keratitis and dacryocystitis with chlamydia trachomatis, Diplococcus gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, hemophilus influenzae or Listera spp; Infect relevant dissemination mycobacterium tuberculosis avium syndrome (MAC) with mycobacterium tuberculosis avium or Mycobacterium intracellulare; Infect relevant gastro-enteritis with campylobacter jejuni; Infect relevant intestinal protozoa disease with Cryptosporidium (Cryptosporidium spp.); Infect relevant odontogenic infection with viridans streptococci; Infect relevant persistence cough with bordetella pertussis; The gas gangrene relevant with clostridium perfringens or infection due to Bacteroides; With atherosclerosis or the cardiovascular disorder relevant with infection involving chlamydia pneumoniae.The animal bacterial infection that can be treated or prevent comprises and pasteurella hemolytica, pasteurella multocida, Mycoplasma bovis or the relevant ox respiratory disease of Bordetella spp with protozoal infections and the illness relevant with these infection; Infect relevant cow intestinal disease with bacillus coli or protozoon (being coccidia, Cryptosporidium etc.); Infect relevant dairy cow mastitis with streptococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, Klebsiella pneumoniae, corynebacterium or faecalis; The pig respiratory disease relevant with A.pleuro, pasteurella multocida or mycoplasma infection; Infect relevant chitling disease with the little snake bacterium of bacillus coli, Lawsonia intracellularis, salmonella or swine dysentery; The foot rot of cattle relevant with Fusobacterium spp; Infect relevant cow metritis with bacillus coli; Infect relevant cow hairy warts with actinomyces pseudonecrophorus or Bacteroides nodosus; Infect relevant cow pink-eye with hemophilus bovis; Infect relevant cow premature labor with protozoon (being neospora (neosporium)); Infect relevant dog and cat urinary tract infection with bacillus coli; Infect relevant dog and cat skin skin and soft tissue infection with staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative staphylococcus (coagulase neg.Staph.) or pasteurella multocida; With infect relevant dog and cat tooth or oral cavity infection with Alcaligenes, bacterioide, clostridium, enterobacteria, eubacterium, Peptostreptococcus, porphyromonas or prevotella.According to method of the present invention, other infectation of bacteria that can be treated or prevent infects relevant illness referring to the 26th edition (antimicrobial therapy company 1996) (" The Sanford Guide To Antimicrobial Therapy " such as J.P.Sanford " Sanford antimicrobial therapy guide " with protozoal infections and with these, 26thEdition, Antimicrobial Therapy, Inc., 1996).
The present invention also relates to following formula: compound Or its pharmacy acceptable salt; Wherein the dotted line between 10 and 11 is represented optional double bond; A is 0 or 1; R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be N 3, R 10NH, R 10C (O) NH, R 10NHC (O) NH, R 10NHC (S) NH, R 10NHNHC (O) NH, R 10ONHC (O) NH or R 10OC (O) NH, R wherein 10Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl; Perhaps R 3Be R 14(C 2-C 4) alkynyl, R wherein 11Be (C 1-C 6) alkyl, (C 6-C 10) alkyl (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl; Perhaps R 3Be R 12R 13N, R wherein 12And R 13Be hydrogen, (C independently of one another 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl;
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement;
Its condition is if a is zero, then R 1Be hydrogen.
The present invention also relates to following formula: compound
Figure A9981294100291
Wherein a is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl independently are selected from halogen, (C by one to three alternatively 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Substituting group replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be NH 2, N 3, O=C=N or S=C=N;
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement.
The present invention also relates to the following formula midbody compound
Figure A9981294100301
Wherein a is 0 or 1; R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be NH 2Or N 3
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement.
The present invention also relates to following formula: compound
Figure A9981294100321
Wherein a is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement.
Detailed description of the invention
Following reaction process is set forth the preparation of The compounds of this invention.Unless otherwise specified, a, the R in reaction process and the subsequent discussion 1, R 2, R 3, R 4, R 5And R 6Define the same.
Preparation A
Figure A9981294100331
Preparation A (continuing)
Figure A9981294100341
Preparation B
Figure A9981294100351
Preparation C
Flow process 1
Flow process 2
Flow process 3
Figure A9981294100391
Flow process 4
Figure A9981294100401
Flow process 5
Flow process 6
Figure A9981294100421
Flow process 7
Flow process 8
Flow process 9
Flow process 10
Figure A9981294100461
Flow process 11
Flow process 12
Figure A9981294100471
In the reaction 1 of preparation A, formula VII compound is converted into corresponding formula VI ketene diacetal compound; R among the formula VII 22Be good leavings group, for example (C 1-C 6) alkane sulfonyloxy, (C 6-C 10) arylsulfonyloxy, (C 1-C 6) acyloxy or imidazoles ketonic oxygen base, method for transformation is in the presence of a kind of polar aprotic solvent, for example acetonitrile, dimethyl formamide, tetrahydrofuran (THF), be preferably acetonitrile, with a kind of alkaline purification of VII, for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, ethyl diisopropylamine, triethylamine, hexamethyl two silicon Lithium Azides or hexamethyl two silicon potassium azide are preferably 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.With reactant about 20 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, stir about was preferably about 2 hours to about 6 hours time phase in 0.5 hour.
In the reaction 2 of preparation A, formula VI ketene diacetal compound is converted into corresponding formula V trinitride, method be a kind of lewis acidic in the presence of, for example tin chloride (IV), titanium chloride (IV), boron trifluoride diethyl ether compound or aluminum chloride, be preferably tin chloride (IV), and in the presence of a kind of aprotonic solvent, make VI and a kind of azide agent reaction, for example azido-trimethyl silicane, sodiumazide or tributyl azide tin are preferably the azido-trimethyl silicane.The solvent that is fit to comprises methylene dichloride, ethylene dichloride, chloroform or tetracol phenixin, is preferably methylene dichloride.Be reflected at approximately-78 ℃ to about 25 ℃ temperature, be preferably about 0 ℃, carry out about 3 hours, be preferably about 6 hours to about 12 hours time phase.
In the reaction 3 of preparation A, formula V trinitride is converted into corresponding formula IV aminocompound, method is in the presence of hydrogen and a kind of catalyzer, for example palladium-carbon, palladium-lime carbonate, platinum oxide (IV) or ruthenium-carbon, be preferably palladium-lime carbonate, and in the presence of a kind of solvent, for example ethanol, methyl alcohol or ethyl acetate, be preferably ethanol, reduction V.Be reflected at about 1psi to the pressure of about 50psi, be preferably about 20psi,, be preferably about 25 ℃, carry out 1 hour extremely about 6 hours time phase, be preferably about 2.5 hours at about 0 ℃ extremely under about 50 ℃ temperature.
In the reaction 4 of preparation A, formula IV aminocompound is converted into corresponding formula XXII isocyanate compound, method is in the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF) Huo diox makes the reaction of IV and phosgene or triphosgene.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 0 ℃, carry out 0.5 hour to about 12 hours time phase, be preferably about 2 hours.
In the reaction 5 of preparation A, formula V compound is converted into corresponding formula IX compound, and method is in ethanol, tetrahydrofuran (THF) Huo diox, heating V to about 30 ℃ to about 100 ℃ temperature, be preferably about 70 ℃, carry out about 0.5 hour, be preferably about 2 hours to about 6 hours time phase.
In the reaction 6 of preparation A, formula IX trinitride is converted into corresponding formula VIII aminocompound, reacts 3 described steps and carries out according to above preparing A.
In the reaction 1 of preparation B, formula VIII aminocompound is converted into corresponding formula XIII isocyanate compound, reacts 4 described steps and carries out according to above preparing A.
In the reaction 1 of preparation C, formula VI ketene diacetal compound is converted into corresponding formula XXXIX compound, works as R 4By one or two nitro, R 14O 2During methylene radical that C or cyano group replace, method for transformation is in the presence of a kind of alkali, for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, triethylamine, sodium hydride or two (trimethyl silyl) lithium amide, be preferably 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), acetonitrile or dimethyl formamide, be preferably acetonitrile, make VI and formula R 4The reaction of H compound.Be reflected at approximately-20 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, carry out about 0.5 hour, be preferably about 2 hours to about 6 hours time phase.
In the reaction 1 of flow process 1, formula IV aminocompound is converted into corresponding formula X amide compound, and method is in the presence of a kind of alkali, and for example pyridine or triethylamine make IV and formula R 10The reaction of-CO-X compound, X wherein is chlorine, bromine or a kind of acid anhydrides.The solvent that is fit to comprises methylene dichloride, ethylene dichloride, tetrahydrofuran (THF) Huo diox, is preferably tetrahydrofuran (THF).With reactant about 0 ℃ to about 50 ℃ temperature, be preferably about 0 ℃, stir about was preferably about 12 hours to about 24 hours time phase in 1 hour.The reaction of production X compound acid amides also can be carried out like this, in the presence of a kind of dewatering agent, and for example 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide makes IV and formula R 10The reaction of-COOH carboxylic acid cpd.
In the reaction 2 of flow process 1, formula IV aminocompound is converted into corresponding formula XI carbamide compound, and method is in the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF) Huo diox makes the reaction of IV and phosgene or triphosgene.In the presence of tetrahydrofuran (THF), diox or dimethyl formamide, with formula R 10NH 2Amine join in the formed reaction mixture.Be reflected at about 0 ℃ to about 100 ℃ temperature, be preferably about 65 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 6 hours.The reaction of the urea of production XI compound also can be carried out like this, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), diox or dimethyl formamide make IV and formula R 10The reaction of N=C=O compound.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 12 hours.
In the reaction 3 of flow process 1, formula IV aminocompound is converted into corresponding formula XII carbamate compounds, and method is in the presence of a kind of alkali, for example triethylamine, pyridine or ethyl diisopropylamine, and in the presence of a kind of aprotonic solvent, make IV and formula R 10The reaction of COCl chloro-formic ester.The solvent that is fit to comprises tetrahydrofuran (THF), diox or dimethyl formamide.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 6 hours.Formula XII compound also can prepare like this, makes formula XXII compound and formula R 10The reaction of OH alcohol.
In the reaction 4 of flow process 1, formula IV aminocompound is converted into corresponding formula XIII compound, and method is in the presence of a kind of catalyzer, and for example palladium-carbon utilizes formula R 10CHO aldehydes or ketones and a kind of reductive agent, for example sodium cyanoborohydride, sodium triacetoxy borohydride or hydrogen carry out the reductive amination of IV.The solvent that is fit to comprises ethanol or methyl alcohol.With reaction mixture about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, stir about was preferably about 12 hours to about 24 hours time phase in 0.5 hour.
In the reaction 1 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XIV compound, method is in the presence of a kind of acid, for example tin chloride (IV), titanium chloride (IV), titanium isopropylate (IV) or boron trifluoride diethyl ether compound, and in the presence of a kind of aprotonic solvent, for example methylene dichloride and ethylene dichloride make VI and formula R 10The reaction of-OH alkylol cpd.Be reflected at approximately-78 ℃ to the temperature of room temperature, be preferably about 0 ℃, carry out about 1 hour, be preferably about 6 hours to about 24 hours time phase.
In the reaction 2 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XV compound, method is in the presence of a kind of acid, for example tin chloride (IV), titanium chloride (IV), titanium isopropylate (IV) or boron trifluoride diethyl ether compound, and in the presence of a kind of polar aprotic solvent, for example methylene dichloride makes VI and formula R 10The reaction of-SH mercaptan compound.Be reflected at approximately-78 ℃ to the temperature of room temperature, be preferably about 0 ℃, carry out about 1 hour, be preferably about 6 hours to about 24 hours time phase.
In the reaction 3 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XVI cyano compound, method is in the presence of a kind of acid, tin chloride (IV) for example, and in the presence of a kind of aprotonic solvent, for example methylene dichloride and ethylene dichloride make the reaction of VI and trimethyl silyl cyanogen or tetrabutyl ammonium cyanide.Be reflected at approximately-78 ℃ to the temperature of room temperature, be preferably about 0 ℃, carry out about 1 hour, be preferably about 6 hours to about 24 hours time phase.
In the reaction 4 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XVII compound, method is in the presence of a kind of acid, tin chloride (IV) for example, and in the presence of a kind of aprotonic solvent, for example methylene dichloride, ethylene dichloride, tetrahydrofuran (THF) Huo diox make VI and trimethyl silyl lsothiocyanates react about 1 hour to about 24 hours time phase, are preferably about 6 hours.In the presence of tetrahydrofuran (THF), diox or dimethyl formamide, with formula R 10NH 2Amine join in the formed reaction mixture.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 6 hours.
In the reaction 1 of flow process 3, formula VIII aminocompound is converted into corresponding formula XVIII amide compound, carries out according to flow process 1 reaction 1 described step above.
In the reaction 2 of flow process 3, formula VIII aminocompound is converted into corresponding formula XIX carbamide compound, carries out according to flow process 1 reaction 2 described steps above.
In the reaction 3 of flow process 3, formula VIII aminocompound is converted into corresponding formula XX carbamate compounds, carries out according to flow process 1 reaction 3 described steps above.
In the reaction 4 of flow process 3, formula VIII aminocompound is converted into corresponding formula XXI compound, carries out according to flow process 1 reaction 4 described steps above.
In the reaction 1 of flow process 4, formula XXII isocyanate compound is converted into corresponding formula XXIII compound, and method is in the presence of a kind of aprotonic solvent, and for example tetrahydrofuran (THF), diox or dimethyl formamide make XXII and formula R 19ONH 2The compound reaction.Be reflected at about 0 ℃ to about 100 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 6 hours.
In the reaction 2 of flow process 4, formula XXIII compound is converted into corresponding formula XIV ring carbamide compound, method is to be with or without under the existence of potassium hydroxide, sodium hydroxide, potassium tert.-butoxide or acetate and a kind of solvent, and for example toluene, benzene or dimethyl formamide heat XXIII.Be reflected at about 25 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 3 hours.
In the reaction 1 of flow process 5, formula XI carbamide compound is converted into corresponding formula XXV ring carbamide compound, carries out according to flow process 4 reactions 2 described steps above.
In the reaction 1 of flow process 6, formula IV ketene diacetal compound is converted into corresponding formula XXVI isothiocyanic acid ester cpds, method be a kind of lewis acidic in the presence of, for example tin chloride (IV), titanium chloride (IV), boron trifluoride diethyl ether compound or aluminum chloride, be preferably tin chloride (IV), and in the presence of a kind of aprotonic solvent, make the reaction of IV and trimethyl silyl lsothiocyanates.The solvent that is fit to comprises methylene dichloride, ethylene dichloride, chloroform or tetracol phenixin, is preferably methylene dichloride.Be reflected at approximately-78 ℃ to about 50 ℃ temperature, be preferably about 0 ℃, carry out about 0.5 hour, be preferably about 12 hours to about 24 hours time phase.
In the reaction 2 of flow process 6, formula XXVI isothiocyanic acid ester is converted into corresponding formula XXVII thiourea compound, carries out according to flow process 1 reaction 2 described steps above.
In the reaction 3 of flow process 6, formula XXVII thiourea compound is converted into corresponding formula XXVIII aminothiazole quinoline compound, carries out according to flow process 4 reactions 2 described steps above.
In the reaction 1 of flow process 7, formula XXIX ring carbamide compound is converted into corresponding formula XXX compound, and method is in the presence of ethanol or pyridine, makes XXIX and formula NHOR 16The compound reaction.Be reflected at about 25 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, carry out about 1 hour to about 48 hours time phase, be preferably about 24 hours.
In the reaction 2 of flow process 7, formula XXX compound is converted into corresponding formula XXXI compound, and method is in the presence of sodium borohydride and a kind of polar aprotic solvent, and for example methyl alcohol or ethanol are preferably methyl alcohol, make XXX and formula R 19The reaction of CHO aldehyde cpd.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 12 hours.
In the reaction 1 of flow process 8, formula XXXII aminocompound is converted into corresponding formula XXXIII compound, method is in the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), diox or methylene dichloride make XXXII and sulphonyl diimidazole, SULPHURYL CHLORIDE or thionyl chloride reaction.Be reflected at approximately-78 ℃ to about 25 ℃ temperature, be preferably about 0 ℃, carry out about 0.5 hour, be preferably about 12 hours to about 24 hours time phase.In the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), diox or methylene dichloride are with formula R 17NH 2Amine join in the formed reaction mixture.Be reflected at about 0 ℃ to about 25 ℃ temperature, be preferably about 0 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 6 hours.
In the reaction 2 of flow process 8, formula XXXIII compound is converted into corresponding formula XXXIV compound, method be with or without potassium tert.-butoxide or acetate in the presence of, in tetrahydrofuran (THF) or dimethyl formamide, heat XXXIII.Be reflected at about 60 ℃ to about 100 ℃ temperature, be preferably about 85 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 2 hours.
In the reaction 1 of flow process 9, formula XIII compound is converted into corresponding formula XXXV compound, carries out according to flow process 4 reactions 1 described step above.
In the reaction 2 of flow process 9, formula XXXV compound is converted into corresponding formula XXXVII compound, and method is to make XXXV and formula R 10CHO aldehyde and the reaction of a kind of reductive agent, for example sodium cyanoborohydride.The solvent that is fit to comprises methyl alcohol, ethanol or ethylene dichloride.With reaction mixture about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, stir about was preferably about 12 hours to about 24 hours time phase in 0.5 hour.
In the reaction 1 of flow process 10, formula XIII isocyanate compound is converted into corresponding formula XXXVI compound, carries out according to flow process 4 reactions 1 described step above.
In the reaction 1 of flow process 11, formula XXVII thiourea compound is converted into corresponding formula XXXVIII cyclic thiourea compound, carries out according to flow process 4 reactions 2 described steps above.
In the reaction 1 of flow process 12, formula XXIX compound is converted into corresponding formula XXXX compound, carries out according to flow process 9 reactions 2 described steps above.
Formula VII initial compounds can be according to United States Patent (USP) 5543400 described method preparations.R wherein 1Be that not isoplastic formula VII initial compounds can be according to WO 98/09978 described method preparation.
The The compounds of this invention of alkalescence can form multiple different salt with various inorganic and organic acids.Although these salt must be pharmaceutically acceptable to animals administer, but also often need the initial pharmaceutically unacceptable salt that from reaction mixture, separates The compounds of this invention in practice, processing by alkaline reagents then, simply the latter is converted into the free alkali cpd, subsequently latter's free alkali is converted into pharmaceutically-acceptable acid addition.The acid salt of alkali cpd of the present invention is easy to prepare, and method is in a kind of water-containing solvent medium or suitable organic solvent, and for example methyl alcohol or ethanol are handled this alkali cpd with being essentially normal selected inorganic or organic acid.Evaporating solvent is easy to obtain required solid salt carefully.Required hydrochlorate also can be precipitated out from the solution of free alkali organic solvent, and method is to add suitable inorganic or organic acid in this solution.
The tart The compounds of this invention can form alkali salt with various pharmaceutically acceptable positively charged ions.The example of these salt comprises the salt of basic metal or alkaline-earth metal, definitely is sodium salt and sylvite.These salt all prepare by common process.The chemical bases that is used to prepare pharmaceutically acceptable alkali salt of the present invention as reagent is to form those of nontoxic alkali salt with acidic cpd of the present invention.Nontoxic alkali salt like this comprise from pharmaceutically acceptable positively charged ion deutero-those, for example sodium, potassium, calcium and magnesium etc.These salt can be easy to preparation, and method is that corresponding acidic cpd is handled with containing the required pharmaceutically acceptable cationic aqueous solution, evaporates gained solution then to doing, preferably under reduced pressure.Perhaps, they also can prepare like this, the low-grade alkane alcohol solution and the required alkali metal alcoholate of acidic cpd is mixed together, then by aforementioned same way as evaporation gained solution to doing.In two kinds of methods, preferably adopt the reagent of stoichiometric quantity, purpose be guarantee to react completely and the yield of required end product the highest.
The compounds of this invention is proved by the ability that this compound suppresses defined human pathogen (measuring I) or animal pathogen (measuring II and III) strain growth the activity of antibacterium and protozoon pathogenic agent.
Measure I
Following mensuration I adopts ordinary method and criteria for interpretation, through design, can provide the direction of chemically modified, and this chemically modified can make compound evade clear and definite macrolide resistance mechanism.Measure among the I, collect one group of bacterial isolates, comprise all types of target cause of disease kind, comprising by the representative of the macrolide resistance mechanism of characterized.Use of this group bacterial strain can be set up chemical structure/activity relationship, measures effectiveness, activity profile and structural element or may be necessary modification to getting rid of resistance mechanism.The bacterial pathogens that comprises the screening group is listed in the following table.As a rule, macrolide susceptibility parent bacterial strain and all be utilizable from its deutero-macrocyclic lactone bacterial strain is to provide the estimating more accurately of ability of evading resistance mechanism about compound.The bacterial strain tolerance macrolide, lincosamides and the Streptogramin B microbiotic that contain the gene of ermA/ermB/ermC by name, this is owing to the modification (methylate) of Erm methylase to the 23SrRNA molecule, thereby has generally prevented the combination of whole three kinds of structure types.Described in two types macrolide effluent: the msrA coding staphylococcus effluent system and prevented the component that macrolide and streptogramin enter, and as if the mefA/E coding only flow out the transmembrane protein of macrolide.The inactivation of macrolide antibiotic may take place, and the cracking (esterase) of phosphorylation of 2 '-hydroxyl (mph) or macrolide can both mediate this deactivation.Utilize conventional polymerase chain reaction (PCR) technology and/or, can carry out characterized bacterial strain by the order-checking of resistance determiner.Round pcr application in this application is referring to " PCR is to the detection of erythromycin resistance determiner " " biocide and chemotherapy " such as J.Sutcliffe (" Detection Of Erythromycin-Resistant DeterminantsBy PCR ", Antimicrobial Agents and Chemotherapy) 40 (11), 2562-2566 (1996).Be determined in the microtiter plates and carry out, explain with reference to PerformanceStandards for Antimicrobial Disk Susceptibility Tests-Sixth Edition; Approved Standard is published by guidance group of standard committee of national clinical labororatory (NCCLS); Relatively to the minimum inhibitory concentration (MIC) of bacterial strain.At first compound is dissolved in dimethyl sulfoxide (DMSO) (DMSO), as the 40mg/ml stock solution.
Strain name Macrocyclic lactone mechanism
Streptococcus aureus 1116 The susceptibility parent
Streptococcus aureus 1117 ????ermB
Streptococcus aureus 0052 The susceptibility parent
Streptococcus aureus 1120 ????ermC
Streptococcus aureus 1032 MsrA, mph, esterase
Staphylococcus haemolyticus 1006 ????msrA、mph
Streptococcus pyogenes 0203 The susceptibility parent
Streptococcus pyogenes 1079 ????ermB
Streptococcus pyogenes 1062 The susceptibility parent
Streptococcus pyogenes 1061 ????ermB
Streptococcus pyogenes 1064 ????ermB
Streptococcus agalactiae 1024 The susceptibility parent
Streptococcus agalactiae 1023 ????ermB
Streptococcus pneumoniae 1016 Susceptibility
Streptococcus pneumoniae 1046 ????ermB
Streptococcus pneumoniae 1095 ????ermB
Streptococcus pneumoniae 1175 ????mefE
Streptococcus pneumoniae 0085 Susceptibility
Hemophilus influenzae 0131 Susceptibility
Moraxella catarrhalis 0040 Susceptibility
Moraxella catarrhalis 1055 The medium tolerance of erythromycin
Bacillus coli 0266 Susceptibility
Measure the activity that II is used to test the antagonism pasteurella multocida, measure the activity that III is used to test the antagonism pasteurella hemolytica.
Measure II
The basis of this mensuration is the liquid diluting method of microlitre form (format).With the single colony inoculation of pasteurella multocida (59A067 bacterial strain) in 5ml brain heart infusion (BHI) meat soup.Test compound is such preliminary, and the 1mg compound is dissolved in 125 μ l dimethyl sulfoxide (DMSO) (DMSO).Utilize nonvaccinated BHI meat soup to prepare the diluent of test compound.The concentration range of used test compound gets by the twice serial dilution from 200 μ g/ml to 0.098 μ g/ml.BHI through the pasteurella multocida inoculation dilutes with nonvaccinated BHI meat soup, obtains 10 4The per 200 μ l of individual cell suspension.The BHI cell suspension is mixed with the various serial dilutions of test compound, cultivated 18 hours down at 37 ℃.Concentration when minimum inhibitory concentration (MIC) equals compound the growth of pasteurella multocida is showed 100% restraining effect, this measures by comparing with nonvaccinated contrast.
Measure III
The basis of this mensuration is the agar dilution that utilizes Steers Replicator to be carried out.Separate two to five bacterium colonies from agar plate, be seeded among the BHI,, shake it (200rpm) simultaneously 37 ℃ of following overnight incubation.The next morning, the pre-culture of pasteurella hemolytica that 300 μ l are fully grown is seeded in the fresh BHI meat soup of 3ml, cultivates down at 37 ℃, shakes it (200rpm) simultaneously.An amount of test compound is dissolved in ethanol, prepares a series of twice serial dilutions.The BHI agar of the various serial dilutions of 2ml with the 18ml fusing is mixed, solidify.When the pasteurella hemolytica culture of being inoculated reaches the 0.5McFarland standard density, utilize Steers Replicator that about 5 μ l pasteurella hemolytica cultures are seeded on the BHI agar plate that contains various concentration test compounds, cultivated 18 hours down at 37 ℃.The initial concentration scope of test compound is 100-200 μ g/ml.Concentration when MIC equals test compound the growth of pasteurella hemolytica is showed 100% restraining effect, this measures by comparing with nonvaccinated contrast.
The activity in vivo of formula I compound can be measured by the protection of animal research of routine, and these researchs are well known to those skilled in the art, carry out in mouse usually.
According to the arrival order mouse is distributed in (10 in every cage) in the cage, minimum 48 hours adaptation time is arranged before the use.Animal intraperitoneal inoculation 0.5ml 3 * 10 3CFU/ml bacterial suspension (pasteurella multocida 59A006 bacterial strain).Each experiment has at least 3 non-administration control groups, comprises one group with the infection of 0.1X challenge dose, uses the 1X challenge dose to infect for two groups; Also can adopt the 10X attack bacteria to infect data set.Usually, all mouse in a given research all in 30-90 minute by infectation of bacteria, especially using repeatedly syringe (for example Cornwall  syringe) to carry out under the situation of infectation of bacteria.Infectation of bacteria began back 30 minutes, carried out the compounds for treating first time.If all animals all by infectation of bacteria, may need second people to begin compound administration when finishing in 30 minutes.Route of administration is subcutaneous or oral.The subcutaneous administration position is at the lax skin of neck dorsal part, and oral administration is undertaken by the syringe needle of feeding.In both cases, the medication volume of every mouse is 0.2ml.30 minutes, 4 hours and 24 hours are with compound administration behind infectation of bacteria.The control compound of known effect is also included within each test by identical administration.Observe animal every day, write down every group survival quantity.Proceed 96 hours (four days) of pasteurella multocida model monitoring behind the aggressive infectation of bacteria.
Calculate PD 50, under this dosage, the compound of being tested is protected the 50% dead because of infectation of bacteria of one group of mouse, is not having under the situation of pharmacological agent, and this infectation of bacteria will be fatefulue.
Formula I compound and pharmacy acceptable salt thereof (hereinafter referred to as " active compound ") can be used for the treatment or the prevention of bacterium or protozoal infections by oral, parenteral, part or rectum administration.In general, the most desirable dosage scope of these compounds from the every kg body weight of about 0.2mg every day (mg/kg/ days) to about 200mg/kg/ days, divide single or multiple administration (being administration every day 1 to 4 time), but, also can carry out necessary adjustment according to curee's kind, body weight and condition and selected specific administration approach.But, the most preferably adopt about 4mg/kg/ days to about 50mg/kg/ days dosage level.Nonetheless, according to the kinds of the Mammals of being treated, fish or birds and to the reaction and the selected types of drug preparations of described medicine and carry out the time of administration stage with at interval, can also adjust.In some cases, the dosage level that is lower than above-mentioned scope lower limit may be more suitable, and in other cases, can adopt bigger dosage, and can not cause any deleterious side effect, as long as earlier this heavy dose is divided into some low doses, administration gets final product in whole day.
Active compound can combine administration separately or with pharmaceutically acceptable carrier or thinner, route of administration as mentioned above, and administration can divide single agent or multi-agent to carry out.Or rather, active compound can be with multiple different formulation administration, that is to say that they can be combined into tablet, capsule, lozenge, dragee, hard candy agent, powder agent, sprays, creme, salve, suppository, jelly, gelifying agent, paste, lotion, ointment, aqueous suspensions, injection solution, elixir, syrup etc. with various pharmaceutically acceptable inert supports.Such carrier comprises solid diluent or weighting agent, sterile aqueous media and various nontoxic organic solvents etc.And combination of oral medication can suitably be given sweet taste and/or flavoring.In general, the concentration level scope of active compound in these formulations is from about 5.0 weight % to about 70 weight %.
About oral administration, can adopt tablet, wherein contain various vehicle, for example Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and glycine, with various disintegrating agents, for example starch (being preferably corn, potato or tapioca (flour)), alginic acid and some composition silicate, and Granulating Bonding Agent, for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic.In addition, for the purpose of compressing tablet, lubricant also is very useful, for example Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum.The solids composition that can also adopt similar type is as the weighting agent in the capsule; Preferred in this respect material also comprises lactose or toffee and macromolecule polyethylene glycol.When oral administration needs aqueous suspensions and/or elixir, active compound can combine with various sweeting agents or correctives, coloring material or stain, if necessary, also has emulsifying agent and/or suspension agent, and thinner, for example water, ethanol, propylene glycol, glycerine and various combination thereof.
About administered parenterally, can adopt the solution of active compound in sesame oil or peanut oil or aqueous propylene glycol.If necessary, the aqueous solution should suitably be cushioned (preferably pH is greater than 8), and at first gives liquid diluent with isotonicity.These aqueous solution are suitable for the purpose of intravenous injection.Oil solution is suitable for intra-arterial, intramuscular and hypodermic purpose.According to standard pharmaceutical technology well known by persons skilled in the art, be easy to realize the preparation of all these solution under aseptic condition.
In addition, also may be with active compound topical of the present invention, according to the standard pharmaceutical practice, this can be undertaken by creme, jelly, gelifying agent, paste, patch, ointment etc.
About to the animals administer except that the people, for example ox or domestic animal, active compound can be in animal-feed administration or as the administration of drencs composition oral.
Active compound also can be with the form administration of liposome release system, and for example monolayer vesicle, large unilamellar vesicles and multilayer are steeped.Liposome can generate from various phosphatide, for example cholesterol, stearylamine or phosphatidylcholine.
Active compound also can with soluble polymer coupling, for example orientable pharmaceutical carrier.Such polymkeric substance can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl MAAm phenyl, poly-hydroxyethyl asparagine-phenol or the polyoxyethylene-polylysine that is replaced by the palmityl residue.In addition, active compound can with a class Biodegradable polymeric coupling, can be used for realizing that controlled delivery of pharmaceutical agents discharges, for example the multipolymer of poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid, poly epsilon caprolactone lactone, polyhydroxybutyrate, poe, polyacetal, gather dihydropyrane, polybutylcyanoacrylate and crosslinked or amphipathic hydrogel segmented copolymer.
The following example is set forth the embodiment of invention, but the present invention is not limited to the scope of the concrete illustration of embodiment.
Embodiment 1
(a is 1 to formula XIII; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α or β; R 4It is the nitro methyl; R 6Be ethyl)
With 1, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (76 μ l, (a is 1 0.5mmol) to join formula VII; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 3It is the imidazoles carbonyl; R 4Be hydrogen; R 6Be ethyl) (71mg, 0.1mmol) (76 μ l are in 2ml acetonitrile solution 0.5mmol) with Nitromethane 99Min..
Gained solution refluxed 1.5 hours under nitrogen.(10ml) joins in the reaction mixture with ethyl acetate, and organic layer washs with saturated sodium dihydrogen phosphate.
Ethyl acetate solution salt water washing is through Na 2SO 4Dry.The gained resistates is through silica gel chromatography (TLC, 5%MeOH-0.5%NH behind the evaporating solvent 4OH-CH 2Cl 2) obtain 19mg (29%) title compound (the C-8 methyl is α); MS m/e 655 (M+1) and 11mg (17%) title compound (the C-8 methyl is β); MS m/e 655 (M+1)
Embodiment 2
(a is 1 to formula VI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α or β; R 6Be ethyl)
With 1, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (90 μ l, (a is 1 0.61mmol) to join formula VII; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 3It is the imidazoles carbonyl; R 4Be hydrogen; R 6Be ethyl) (4.30g is in 120ml anhydrous acetonitrile 6.1mmol).
Solution refluxed 4 hours.Evaporating solvent, resistates obtains 2.44g (67%) title compound (the C-8 methyl is α) and 643mg (18%) title compound (the C-8 methyl is β) through silica gel chromatography (1% methyl alcohol-0.5% triethylamine-methyl tertiary butyl ether); MS m/e 594 (M+1)
Embodiment 3
(a is 1 to formula V; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6Be ethyl)
(a is 1 with formula VI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6Be ethyl) (555mg, 0.94mmol) compound is dissolved in 40ml ethene, is cooled to-78 ℃.Drip trimethyl silyl trinitride (dichloromethane solutions of 744 μ l 1M tin chlorides (IV)).Reaction mixture slowly is warmed to room temperature, and stirring is spent the night.Add saturated sodium bicarbonate solution and make the reaction all standing, the product dichloromethane extraction.Dichloromethane layer salt water washing is through dried over sodium sulfate.Evaporating solvent, resistates obtains 410mg (69%) title compound through chromatogram; MS m/e 637 (M+1)
Embodiment 4
(a is 1 to formula X; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be methyl) and formula XVIII (a is 1; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be methyl)
Lin Dele (Lindlar) catalyzer (25mg) is joined formula V, and (a is 1; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6Being ethyl) (25mg, in 5ml ethanolic soln 0.039mmol), gained solution is used 20psi hydrogen hydrogenation at room temperature 2 hours to compound in the Parr wobbler.Solution is by diatomite filtration, evaporating solvent.Resistates is dissolved in the 2ml tetrahydrofuran (THF), handles down at 4 ℃ with 50 μ l pyridines and 50 μ l diacetyl oxides and spend the night.Evaporating solvent and excess reagent, resistates is by silica-gel plate chromatogram (5% methyl alcohol-0.5%NH 4OH-CH 2Cl 2) obtain 6.6mg (26%) formula X; MS m/e 653 (M+1) and 2.7mg (11%) formula XVIII; MSm/e 653 (M+1)
Embodiment 5
(a is 1 to formula XXIX; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 5It is Alpha-Methyl; R 6Be ethyl) and formula XXXV (a is 1; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6Be ethyl)
Lindlar catalyst (137mg) is joined formula V, and (a is 1; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6Being ethyl) (137mg is in 15ml ethanolic soln 0.215mmol) for compound.The hydrogenation 2 hours under 20psi hydrogen of gained solution.Solution under reduced pressure removes and desolvates by diatomite filtration.Resistates is dissolved in the 5ml tetrahydrofuran (THF), in ice bath, cools off.Add triethylamine (85 μ l, 0.611mmol, 2.84eq) photoreactive gas (0.25ml 1.93M toluene solution, 0.483mmol, 2.24eq).Solution stirred 2 hours down at 0 ℃.Reaction mixture is with the dilution of 25ml ethyl acetate, with saturated sodium bicarbonate solution and salt water washing.
After dried over sodium sulfate, under reduced pressure remove and desolvate.Then resistates is dissolved in the 2ml dimethyl formamide, and the adding anhydrous hydrazine (67 μ l, 2.15mmol, 10eq).Gained solution heated 6 hours down at 60 ℃.Under reduced pressure remove dimethyl formamide, resistates is through SiO 2Chromatogram (5% methyl alcohol-0.5%NH 4OH-CH 2Cl 2) obtain two kinds of integral part.SiO further passes through in first part 2Plate chromatography (7.5%MeOH-0.75%NH 4OH-CH 2Cl 2) obtain 9mg (7%) formula XXIX; MS m/e 627 (M+1)
Second section further passes through SiO 2Plate chromatography (5%MeOH-5% triethylamine-methyl tertiary butyl ether) obtains 12mg (9%) formula XXXV; MS m/e 627 (M+1)
Embodiment 6
(a is 1 to formula L; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 5It is Alpha-Methyl; R 6Be ethyl)
(a is 1 with formula XXIX; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 5It is methyl; R 6Being ethyl) (12m, 0.027mmol) (10mg 0.054mmol) is heated to 90 ℃ and reaches 14 hours compound in 1ml toluene with 3-(quinolyl-4) propionic aldehyde.Under reduced pressure remove toluene, resistates is dissolved in 1ml methyl alcohol (MeOH).Add sodium cyanoborohydride (16.9mg, 0.27mol) and acetate (25 μ l, 0.43mmol), gained solution at room temperature stirred 46 hours.Remove and desolvate, resistates is dissolved in methylene dichloride, with saturated sodium bicarbonate solution and salt water washing.After dried over sodium sulfate, evaporating solvent, resistates is through silica gel chromatography (TLC, 5% methyl alcohol-0.5%NH 4The OH-methylene dichloride) obtains the light yellow glassy mass of 13mg.This material further passes through silica gel chromatography (TLC, 5%MeOH-5% triethylamine-methyl tertiary butyl ether) and obtains 10mg (47%) title compound; MS m/e 839 (M+1)
Embodiment 7
(a is 1 to formula XI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl) and formula XIX (a is 1; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl)
Lindlar catalyst (137mg) is joined formula V, and (a is 1; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6Being ethyl) (137mg is in 15ml ethanolic soln 0.215mmol) for compound.The hydrogenation 2 hours under 20psi hydrogen of gained solution.Solution under reduced pressure removes and desolvates by diatomite filtration.Resistates is dissolved in 5ml THF, in ice bath, cools off.Add triethylamine (85 μ l, 0.611mmol, 2.84eq) toluene solution of photoreactive gas (250 μ l 1.93M solution, 0.483mmol, 2.24eq).Solution stirred 2 hours down at 0 ℃.Reaction mixture is used saturated NaHCO with the dilution of 25ml ethyl acetate 3Solution and salt water washing.Through Na 2SO 4Drying is under reduced pressure removed and is desolvated.Resistates is dissolved in 2ml DMF, and adding 4-(3-pyridyl)-1H-imidazoles-1-butylamine (139mg, 0.645mmol).
Solution is warmed to 60 ℃ and reaches 6 hours.Under reduced pressure remove DMF, resistates is through silica gel chromatography (TLC, 5%MeOH-0.5% NH 4OH-CH 2Cl 2) obtain two parts.The low-pole part is further passed through preparation type SiO 2TLC chromatogram (7.5%MeOH-0.75% NH 4OH-CH 2Cl 2) obtain 5mg (3%) formula XI compound; MS m/e 853 (M+1)
Strong polarity part is further passed through silica gel chromatography (TLC 5% MeOH-5% triethylamine-methyl tertiary butyl ether) and is obtained 12mg (7%) formula XIX compound; MS m/e 853 (M+1)
Embodiment 7B
(a is 1 to formula XXV; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl)
(a is 1 with XI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl) (35mg, 0.041mmol) the 1ml toluene solution with 3.5mg potassium hydroxide heated 1 hour down at 90 ℃.Cooled solution is diluted with ethyl acetate, washes with water.The waterbearing stratum is with fresh ethyl acetate extraction.Organic layer after the merging is through Na 2SO 4Drying, evaporation.Resistates is through silica gel chromatography (TLC 10%MeOH-CH 2Cl 2) obtain 15mg (43%) title compound; MS m/e 853
Embodiment 8
(a is 1 to formula XI; R 1It is methyl; R 2Be hydrogen; The C-8 methyl is α; R 6It is ethyl; R 7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl)
(a is 1 with formula XI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl) compound (6mg, 7mmol) in methyl alcohol warm 1 hour.Evaporate methyl alcohol then, resistates is through silica gel chromatography (TLC 10%MeOH-1%NH 4OH-CH 2Cl 2) obtain 4mg (70%) title compound; MS m/e 812 (M+1)
Embodiment 9
(a is 1 to formula XXVI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α or β; R 5It is methyl; R 6Be ethyl)
(a is 1 with formula VI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α or β; R 6Be ethyl) (54mg 0.091mmol) is dissolved in 5ml CH 2Cl 2, cooling in dry ice-propanone is bathed.(128 μ l, 0.91mmol) and tin chloride (IV) solution (137 μ l 1M dichloromethane solution), gained solution is warmed to ambient temperature overnight gradually to add the trimethyl silyl lsothiocyanates.Add saturated sodium bicarbonate solution then, the product ethyl acetate extraction.Organic layer salt water washing is through dried over sodium sulfate.The gained resistates is through silica gel chromatography (hexane: acetone=2: 1) obtain 10mg (17%) title compound behind the evaporating solvent; MS m/e 653
Embodiment 10
(a is 1 to formula XIV; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α; R 6It is ethyl; R 7Be propargyl)
(a is 1 with formula VI; R 1It is methyl; R 2It is ethanoyl; The C-8 methyl is α or β; R 6Being ethyl) (118mg 0.2mmol) is dissolved in the 10ml anhydrous methylene chloride to compound, is cooled to-78 ℃.Add propargyl alcohol (35 μ l, 0.6mmol) and the dichloromethane solution of 1M tin chloride (IV) (220 μ l, 0.22mmol), solution is warmed to ambient temperature overnight gradually.Add saturated sodium bicarbonate solution and make the reaction all standing, dichloromethane solution salt water washing is through dried over sodium sulfate.The gained resistates is through silica gel chromatography (TLC 5% methyl alcohol-2.5% triethylamine-methyl tertiary butyl ether) behind the evaporation methylene dichloride.Suitable band passes through chromatogram (10% acetone-hexane) once more and obtains 6mg (5%) title compound with 5% methyl alcohol-dichloromethane extraction; MS m/e 649 (M+1)

Claims (24)

1, following formula: compound
Figure A9981294100021
Or its pharmacy acceptable salt; Wherein
Dotted line between 10 and 11 is represented optional double bond;
A is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be amino, cyano group, N 3, R 10NH, R 10C (O) NH, R 10NHC (O) NH, R 10NHC (S) NH, R 10NHNHC (O) NH, R 10ONHC (O) NH, R 10O, R 10OC (O) NH, R 10S (O) n, R 10Phosphinylidyne amino, R 10Sulfonamido, SH, R 10S, n definition wherein is the same, R 10Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl; Perhaps R 3Be R 12R 13N, R wherein 12And R 13Be hydrogen, (C independently of one another 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl;
R 4Be hydrogen, optional by one or two nitro, cyano group, R 14C (O) and R 14The methyl that OC (O) replaces; Perhaps R 4Be N 3, R 14O, R 14NH, R 14S, R wherein 14Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl; Perhaps R 4Be R 15N (C 1-C 6) alkyl, R wherein 15Be hydrogen, (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl;
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
Perhaps R 3And R 4Can form with the carbon that they connected
Figure A9981294100041
Wherein the dotted line between nitrogen in formula II and the variable group W is represented optional double bond;
W is C=O, C=S, SO 2Or C=NR 10, R wherein 10Define the same;
Y is oxygen, sulphur or NR 17, R wherein 17Be hydrogen, R 19, R 19O or R 19NH, R wherein 19Be hydrogen, (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 5-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 18Be hydrogen, (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, aryl wherein and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 20R 21N, R 20C (O), R 20C (O) O, R 20OC (O), R 20C (O) NH, R 20NHC (O), R 20R 21NC (O) and R 20OC (O) 2, R wherein 20And R 21Be hydrogen, optional quilt (C independently of one another 6-C 10) acyl group or (C 5-C 10) (the C that replaces of aryl 1-C 6) alkyl or (C 2-C 9) heteroaryl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement;
Its condition is R 17Or R 18Have at least one to be hydrogen;
If its condition is dotted line representative two key, then R between 10 and 11 4Be hydrogen;
Its condition is if a is zero, then R 1Be hydrogen.
2, according to the compound of claim 1, wherein a is 1 and R 1Be (C 1-C 10) alkyl.
3, according to the compound of claim 1, R wherein 2Be hydrogen.
4, according to the compound of claim 1, R wherein 3Be N 3, R 10NH, R 10C (O) NH, R 10NHC (O) NH or R 10NHNHC (O) NH.
5, according to the compound of claim 1, R wherein 4Be hydrogen, R 14NH or R 14S.
6, according to the compound of claim 1, R wherein 6It is ethyl.
7, according to the compound of claim 1, wherein W is that C=O and Y are NR 17
8, according to the compound of claim 1, wherein a is 1; R 1Be (C 1-C 10) alkyl; R 2Be hydrogen; R 3Be N 3, R 10NH, R 10C (O), R 10NHC (O) NH or R 10NHNHC (O) NH; R 4Be hydrogen, R 14NH or R 14S and R 6It is ethyl.
9, according to the compound of claim 1, wherein a is 1; R 1Be (C 1-C 10) alkyl; R 2Be hydrogen; R 3And R 4Form formula II compound with the carbon that they connected; W is that C=O and Y are NR 17
10, according to the compound of claim 1, wherein said compound is selected from:
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2,11-(imino-carbonyl (2-(3-(4-quinolyl) propyl group) hydrazono-))-3-oxo erythromycin;
11,12-dideoxy-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11,12-dideoxy-11,12-two dehydrogenations-3-takes off ((2, the 6-dideoxy-own ribose of 3-C-methyl-3-O-methyl-α-L-pyrans-5-yl) oxygen)-6-O-methyl isophthalic acid 0-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo-8-and show erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo-8-erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-pyrans is ribosyl) oxygen)-12-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo-12,11-(imino-carbonyl hydrazono-) erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-imino-carbonyl hydrazono--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-isothiocyanato-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-alkynes propoxy--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate; With
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate.
11, the pharmaceutical composition that is used for Mammals, fish or birds treatment for diseases, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this pharmaceutical composition comprises claim 1 compound and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
12, the pharmaceutical composition of claim 11, wherein said illness are to infect relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and mastoiditis with streptococcus pneumoniae, hemophilus influenzae, Moraxella catarrhalis, streptococcus aureus or peptostreptococcus; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis with streptococcus pyogenes, C family and G family suis, diphtheria clostridium or Actinobacillus haemolyticum; The respiratory tract infection relevant with mycoplasma pneumoniae, legionella pneumophilia, streptococcus pneumoniae, hemophilus influenzae or infection involving chlamydia pneumoniae; With streptococcus aureus, coagulase-positive staphylococci (being staphylococcus epidermidis, staphylococcus haemolyticus etc.), streptococcus pyogenes, streptococcus agalactiae, suis C-F family (minute-colony streptococci), viridans streptococci, minimum coryneform bacteria, clostridium or relevant non-concurrency skin and soft tissue infection, abscess and osteomyelitis and the lochiopyra of Bartonella henselae; Infect relevant uncomplicated acute urinary tract infection with Staphylococcus saprophyticus or faecalis; Urethritis and trachelitis; Infect relevant sexually transmitted disease (STD) with chlamydia trachomatis, Ducrey bacillus, Tyreponema pallidum, Ureaplasma urealyticum or Diplococcus gonorrhoeae; With streptococcus aureus (food poisoning and toxic shock syndrome) or A, the B toxin disease relevant with the streptococcal infection of C family; The ulcer relevant with helicobacter pylori infection; Infect relevant whole body heating syndrome with borrelia obermeieri; Infect relevant Lyme disease with Borrelia burgdofferi; Infect relevant conjunctivitis, keratitis and dacryocystitis with chlamydia trachomatis, Diplococcus gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, hemophilus influenzae or Listera spp; Infect relevant dissemination mycobacterium tuberculosis avium syndrome (MAC) disease with mycobacterium tuberculosis avium or Mycobacterium intracellulare; Infect relevant gastro-enteritis with campylobacter jejuni; The intestinal protozoa disease relevant with Cryptosporidium spp; Infect relevant odontogenic infection with viridans streptococci; Infect relevant persistence cough with bordetella pertussis; The gas gangrene relevant with clostridium perfringens or infection due to Bacteroides; Atherosclerosis or the cardiovascular disorder relevant with Hp or infection involving chlamydia pneumoniae; The ox respiratory disease relevant with pasteurella hemolytica, pasteurella multocida, Mycoplasma bovis or Bordetella spp; The cow intestinal disease relevant with bacillus coli or protozoal infections; Infect relevant dairy cow mastitis with streptococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, Klebsiella pneumoniae, corynebacterium or faecalis; The pig respiratory disease relevant with A.pleuro, pasteurella multocida or mycoplasma infection; Infect relevant chitling disease with the little snake bacterium of bacillus coli, Lawsonia intracellularis, salmonella or swine dysentery; The foot rot of cattle relevant with Fusobacterium spp; Infect relevant cow metritis with bacillus coli; Infect relevant cow hairy warts with actinomyces pseudonecrophorus or Bacteroides nodosus; Infect relevant cow pink-eye with hemophilus bovis; The cow premature labor relevant with protozoal infections; Infect relevant dog and cat urinary tract infection with bacillus coli; Infect relevant dog and cat skin skin and soft tissue infection with staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative staphylococcus or pasteurella multocida; With infect relevant dog and cat tooth or oral cavity infection with Alcaligenes, bacterioide, clostridium, enterobacteria, eubacterium, Peptostreptococcus, porphyromonas or prevotella.
13, the method for treatment Mammals, fish or birds illness, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this method comprises that claim 1 compound with significant quantity on the therapeutics is to described Mammals, fish or birds administration.
14, the method for claim 13, wherein said illness are to infect relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and mastoiditis with streptococcus pneumoniae, hemophilus influenzae, Moraxella catarrhalis, streptococcus aureus or peptostreptococcus; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis with streptococcus pyogenes, C family and G family suis, diphtheria clostridium or Actinobacillus haemolyticum; The respiratory tract infection relevant with mycoplasma pneumoniae, legionella pneumophilia, streptococcus pneumoniae, hemophilus influenzae or infection involving chlamydia pneumoniae; With streptococcus aureus, coagulase-positive staphylococci (being staphylococcus epidermidis, staphylococcus haemolyticus etc.), streptococcus pyogenes, streptococcus agalactiae, suis C-F family (minute-colony streptococci), viridans streptococci, minimum coryneform bacteria, clostridium or relevant non-concurrency skin and soft tissue infection, abscess and osteomyelitis and the lochiopyra of Bartonella henselae; Infect relevant uncomplicated acute urinary tract infection with Staphylococcus saprophyticus or faecalis; Urethritis and trachelitis; Infect relevant sexually transmitted disease (STD) with chlamydia trachomatis, Ducrey bacillus, Tyreponema pallidum, Ureaplasma urealyticum or Diplococcus gonorrhoeae; With streptococcus aureus (food poisoning and toxic shock syndrome) or A, the B toxin disease relevant with the streptococcal infection of C family; The ulcer relevant with helicobacter pylori infection; Infect relevant whole body heating syndrome with borrelia obermeieri; Infect relevant Lyme disease with Borrelia burgdofferi; Infect relevant conjunctivitis, keratitis and dacryocystitis with chlamydia trachomatis, Diplococcus gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, hemophilus influenzae or Listera spp; Infect relevant dissemination mycobacterium tuberculosis avium syndrome (MAC) with mycobacterium tuberculosis avium or Mycobacterium intracellulare; Infect relevant gastro-enteritis with campylobacter jejuni; The intestinal protozoa disease relevant with Cryptosporidium spp; Infect relevant odontogenic infection with viridans streptococci; Infect relevant persistence cough with bordetella pertussis; The gas gangrene relevant with clostridium perfringens or infection due to Bacteroides; Atherosclerosis or the cardiovascular disorder relevant with Hp or infection involving chlamydia pneumoniae; The ox respiratory disease relevant with pasteurella hemolytica, pasteurella multocida, Mycoplasma bovis or Bordetella spp; The cow intestinal disease relevant with bacillus coli or protozoal infections; Infect relevant dairy cow mastitis with streptococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, Klebsiella pneumoniae, corynebacterium or faecalis; The pig respiratory disease relevant with A.pleuro, pasteurella multocida or mycoplasma infection; Infect relevant chitling disease with the little snake bacterium of bacillus coli, Lawsonia intracellularis, salmonella or swine dysentery; The foot rot of cattle relevant with Fusobacterium spp; Infect relevant cow metritis with bacillus coli; Infect relevant cow hairy warts with actinomyces pseudonecrophorus or Bacteroides nodosus; Infect relevant cow pink-eye with hemophilus bovis; The cow premature labor relevant with protozoal infections; Infect relevant dog and cat urinary tract infection with bacillus coli; Infect relevant dog and cat skin skin and soft tissue infection with staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative staphylococcus or pasteurella multocida; With infect relevant dog and cat tooth or oral cavity infection with Alcaligenes, bacterioide, clostridium, enterobacteria, eubacterium, Peptostreptococcus, porphyromonas or prevotella.
15, be used for the pharmaceutical composition of mammalian cancer treatment, this pharmaceutical composition comprises claim 1 compound and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
16, the pharmaceutical composition of claim 15, wherein said cancer is a nonsmall-cell lung cancer.
17, the method for treatment mammalian cancer comprises that 1 compound with significant quantity on the therapeutics is to described Mammals administration.
18, the method for claim 17, wherein said cancer is a nonsmall-cell lung cancer.
19, following formula: compound
Figure A9981294100101
Or its pharmacy acceptable salt; Wherein
Dotted line between 10 and 11 is represented optional double bond;
A is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be N 3, R 10NH, R 10C (O) NH, R 10NHC (O) NH, R 10NHC (S) NH, R 10NHNHC (O) NH, R 10ONHC (O) NH or R 10OC (O) NH, R wherein 10Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl; Perhaps R 3Be R 14(C 2-C 4) alkynyl, R wherein 11Be (C 1-C 6) alkyl, (C 6-C 10) alkyl (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl; Perhaps R 3Be R 12R 13N, R wherein 12And R 13Be hydrogen, (C independently of one another 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl;
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 5-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement;
Its condition is if a is zero, then R 1Be hydrogen.
20, the pharmaceutical composition that is used for Mammals, fish or birds treatment for diseases, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this pharmaceutical composition comprises claim 19 compound and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
21, the method for treatment Mammals, fish or birds illness, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this method comprises that claim 19 compound with significant quantity on the therapeutics is to described Mammals, fish or birds administration.
22, following formula: compound
Wherein a is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl independently are selected from halogen, (C by one to three alternatively 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Substituting group replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be NH 2, N 3, O=C=N or S=C=N;
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement.
23, following formula: compound
Figure A9981294100141
Wherein a is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 3Be NH 2Or N 3
X is oxygen or NOR 16, R wherein 16Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2, R wherein 8And R 9Be hydrogen or optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement.
24, following formula: compound
Figure A9981294100151
Wherein a is 0 or 1;
R 1Be hydrogen or optional by fluorine, cyano group, R 7, R 7O 2C, R 7C (O) NH and R 7S (O) n(the C that replaces 1-C 10) alkyl, n wherein is 0,1 or 2, R 7Be (C 1-C 6) alkyl, (C 2-C 12) alkenyl, (C 2-C 12) alkynyl, (C 3-C 10) cycloalkyl (C 1-C 6) alkyl, (C 2-C 9) Heterocyclylalkyl (C 1-C 6) alkyl, (C 6-C 10) aryl (C 1-C 6) alkyl or (C 2-C 9) heteroaryl (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C 1-C 3) alkoxyl group, hydroxyl, nitro, cyano group, (C 6-C 10) aryl, (C 2-C 9) heteroaryl, R 8R 9N, R 8C (O), R 8C (O) O, R 8OC (O), R 8C (O) NH, R 8NHC (O), R 8R 9NC (O) and R 8OC (O) 2Replace R wherein 8And R 9Be hydrogen, optional quilt (C independently of one another 6-C 10) aryl or (C 2-C 9) (the C that replaces of heteroaryl 1-C 6) alkyl;
R 2Be hydrogen or hydroxy-protective group;
R 5Be hydrogen or methyl;
R 6Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl or (C 1-C 6) alkylthio (C 1-C 6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R 6Be optional quilt (C 1-C 6) (the C that replaces of alkyl or halogen 3-C 10) cycloalkyl or (C 5-C 10) cycloalkenyl group; Perhaps R 6Be optional quilt (C 1-C 6) alkyl, (C 2-C 8) alkenyl, (C 2-C 8) alkynyl, (C 3-C 10) cycloalkyl, (C 5-C 10) (the C that replaces of cycloalkenyl group or aryl 2-C 8) Heterocyclylalkyl or (C 2-C 9) heteroaryl, aryl wherein is alternatively by alkyl, (C 1-C 6) the alkoxy or halogen replacement.
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